UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`
`MICRO LABS LIMITED AND MICRO LABS USA INC.,
`Petitioner,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. AND
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`
`____________
`
`
`Case IPR2017-01434
`U.S. Patent No. 5,886,035
`
`____________
`
`
`SUPPLEMENTAL DECLARATION OF
`TIMOTHY L. MACDONALD, PH.D.
`
`
`
`
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`IPR Page 1/23
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`Santen/Asahi Glass Exhibit 2028
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`____________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`
`MICRO LABS LIMITED AND MICRO LABS USA INC.,
`Petitioner,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. AND
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`
`____________
`
`
`Case IPR2017-01434
`U.S. Patent No. 5,886,035
`
`____________
`
`
`SUPPLEMENTAL DECLARATION OF
`TIMOTHY L. MACDONALD, PH.D.
`
`
`
`
`
`
`
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`IPR Page 1/23
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`Santen/Asahi Glass Exhibit 2028
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`
`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`AN INITIAL INCREASE IN IOP WAS A SERIOUS
`FLAW FOR A POTENTIAL IOP-LOWERING DRUG................................ 2
`
`III.
`
`SECONDARY CONSIDERATIONS ............................................................. 4
`
`A.
`
`Commercial Success/Copying............................................................... 4
`
`B.
`
`C.
`
`Unexpected Results ............................................................................. 13
`
`Long-Felt but Unmet Need ................................................................. 16
`
`D.
`
`Failure of Others .................................................................................. 16
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`
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`i
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`IPR Page 2/23
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`I, Timothy L. Macdonald, Ph.D., declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am Professor of Chemistry, and former Chair of Chemistry, at the
`
`University of Virginia ("UVA"). I also hold a secondary appointment as Professor
`
`of Pharmacology at UVA.
`
`2.
`
`I have been retained on behalf of Patent Owners Santen
`
`Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd. (together, "Patent Owner") as
`
`an independent expert consultant in the above-referenced inter partes review
`
`("IPR") proceeding, to provide information and opinions on the teachings of the
`
`prior art and the state of the art, as relevant to the issued claims of U.S. Patent No.
`
`5,886,035 ("the '035 Patent"). Ex.1001.
`
`3.
`
`I previously submitted a written declaration on these topics, which
`
`was filed as Ex.2001. I hereby incorporate my previous declaration into this
`
`declaration.
`
`4.
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`For purposes of this declaration, I have been asked to explain, as of
`
`December 26, 1996, how a POSITA developing prostaglandin analogs for IOP-
`
`lowering would have viewed an initial increase in IOP caused by a candidate
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`compound.
`
`5.
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`I have also been asked to consider whether objective secondary
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`considerations of nonobviousness (for example, commercial success, copying,
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`1
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`IPR Page 3/23
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`unexpected results, long-felt but unmet need, and failure of others) support the
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`nonobviousness of the claims of the '035 Patent.
`
`6. My opinions in this Declaration are based on documents I have
`
`reviewed in connection with this proceeding, and are further informed by my
`
`knowledge and experience, including my decades of experience in medicinal
`
`chemistry and molecular pharmacology. I have also relied on the Supplemental
`
`Declaration of Robert D. Fechtner, M.D. (Ex.2029), which I understand is also
`
`being submitted in this proceeding. An updated list of the documents and
`
`materials that I considered in connection with the development of my opinions set
`
`forth in this (and my previous) declaration is attached hereto as Exhibit B.
`
`II. AN INITIAL INCREASE IN IOP WAS A SERIOUS
`FLAW FOR A POTENTIAL IOP-LOWERING DRUG
`
`7.
`
`As of December 26, 1996, a POSITA would have recognized that an
`
`initial increase in IOP, as was reported for Compound C of Klimko, was a serious
`
`deficiency in the context of a potential IOP-lowering drug. A POSITA at the time
`
`would also have understood that the initial increase in IOP could not be easily
`
`overcome, for example, by reducing the dose. Rather, a POSITA would have
`
`expected that decreasing the administered dose of Compound C would have the
`
`effect of decreasing the overall efficacy of the drug. This is because the initial
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`increase in IOP is part of a biphasic response to Compound C; the first phase is a
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`2
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`IPR Page 4/23
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`hypertensive phase where IOP is increased, and the second phase is a hypotensive
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`phase where IOP is reduced. See, e.g., Camras et al., "Reduction of intraocular
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`pressure by prostaglandins applied topically to the eyes of conscious rabbits,"
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`Invest. Ophthalmol. Vis. Sci. 16:1125-1134 (1977) ("Camras 1977") (Ex.2003), 2.
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`Given that Klimko does not provide dose-response curves for Compound C, a
`
`POSITA would have expected similar dose-response curves for both phases of the
`
`response to Compound C. While the unacceptable initial increase in IOP could
`
`potentially have been reduced by a low enough dose, a POSITA would have
`
`expected that the later IOP reduction would have been reduced as well. For
`
`example, in Camras 1977 (Ex.2003), 4, PGF2α was shown to exhibit an initial IOP
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`increase after administration. Although the initial IOP increase was mitigated by
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`drastically lowering the dose of PGF2α, the IOP-lowering activity was
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`compromised at those lower doses. Id. At a 200 μg dose, PGF2α provided IOP-
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`lowering activity for at least about a full day, but there was a significant initial
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`increase in IOP after administration. Id. At 50 μg PGF2α, the initial increase in
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`IOP was not reduced. Id. At 5 μg PGF2α, the initial increase in IOP was reduced,
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`but the area under the curve of the IOP-lowering was dramatically reduced, and the
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`duration of efficacy was limited to 15 hours or less (rather than at least about a full
`
`day at 50 μg and 200 μg). Id. In my experience, a POSITA always favored
`
`development of compounds that do not increase IOP over compounds that do
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`
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`3
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`IPR Page 5/23
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`increase IOP (even transiently), especially if the IOP increase is accompanied by
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`other side effects (such as hyperemia). See, e.g., Wang et al., "Effect of 8-iso
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`prostaglandin E-2 on aqueous humor dynamics in monkeys," Arch. Ophthalmol.
`
`116(9):1213-1216 (1998) (Ex.2034), 2 (reporting on an 8-iso PGE2 derivative that
`
`lacks the "initial ocular hypertension" of PGE2).
`
`III. SECONDARY CONSIDERATIONS
`
`8.
`
`Secondary considerations of non-obviousness, including commercial
`
`success, copying, unexpected results, long-felt and unmet need, and failure of
`
`others, further support the non-obviousness of tafluprost.
`
`A. Commercial Success/Copying
`
`9.
`
`Zioptan® and Tapros are Patent Owner's branded tafluprost drugs for
`
`glaucoma and ocular hypertension in the US and Japan/Asia/Europe, respectively.
`
`Ex.2032 (Zioptan® label), 1; Ex.2044 (Tapros medication guide), 1. In my
`
`opinion, both are commercial embodiments of every claim of the '035 Patent. In
`
`particular, both contain 0.0015% tafluprost as the active ingredient. Ex.2032, 1;
`
`Ex.2044, 1.
`
`
`
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`4
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`IPR Page 6/23
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`10. Tafluprost is 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-
`
`tetranor prostaglandin F2α isopropyl ester:
`
`Ex.2032, 4.
`
`
`
`11. As shown in the chart below, the tafluprost-containing Zioptan® and
`
`Tapros medicines meet every limitation of every claim of the '035 Patent:
`
`Claims of U.S. Patent No.
`5,886,035
`
`Claim 1
`A fluorine-containing prostaglandin
`derivative of the following formula (1)
`or a salt thereof:
`
`Zioptan® and Tapros
`
`
`Zioptan® and Tapros contain tafluprost,
`a fluorine-containing prostaglandin
`derivative with the following chemical
`structure, which is encompassed by
`formula (1):
`
`
`
`
`
`5
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`IPR Page 7/23
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`Claims of U.S. Patent No.
`5,886,035
`wherein A is an ethylene group, a
`vinylene group, an ethynylene group, —
`OCH2— or —SCH2—,
`
`Zioptan® and Tapros
`
`Tafluprost contains a vinylene group at
`the A position, as seen below:
`
`R1 is a substituted or unsubstituted
`aryloxyalkyl group,
`
`
`
`
`Tafluprost contains a phenoxymethyl
`group, which is an unsubstituted
`aryloxyalkyl group, at the R1 position,
`as seen below:
`
`each of R2 and R3 which are
`independent of each other, is a hydrogen
`atom or an acyl group, or forms a single
`bond together with Z,
`
`
`
`
`
`Tafluprost contains hydrogen atoms at
`each of the R2 and R3 positions, as seen
`below:
`
`
`
`
`
`6
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`IPR Page 8/23
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`
`
`Claims of U.S. Patent No.
`5,886,035
`X is —CH2—, —O— or —S—,
`
`Zioptan® and Tapros
`
`Tafluprost contains —CH2— at the X
`position, as seen below:
`
`Z is —OR4, —NHCOR5, —NHSO2R6
`or —SR7, or forms a single bond
`together with R2 or R3,
`
`
`
`
`Tafluprost contains an isopropoxy
`group, which is encompassed by —OR4,
`at the Z position, as seen below:
`
`
`
`
`Tafluprost contains an isopropyl group,
`which is an alkyl group, at the R4
`position, as seen below:
`
`each of R4, R5, R6 and R7 which are
`independent of one another, is a
`hydrogen atom, an alkyl group, an
`alkenyl group, an alkynyl group, a
`cycloalkyl group, an aryl group or an
`aralkyl group,
`
`
`
`
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`7
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`IPR Page 9/23
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`Claims of U.S. Patent No.
`5,886,035
`and a dual line consisting of solid and
`broken lines is a single bond, a cis-
`double bond or a trans-double bond.
`
`Zioptan® and Tapros
`
`Tafluprost contains a cis-double bond at
`the dual line in formula (1), as seen
`below:
`
`Claim 2
`The compound according to claim 1,
`wherein R1 is a phenoxymethyl group, a
`3,5-dichlorophenoxymethyl group or a
`3-chlorophenoxymethyl group.
`
`
`
`
`
`See claim 1.
`Tafluprost contains a phenoxymethyl
`group at the R1 position, as seen below:
`
`Claim 3
`The compound according to claim 1,
`
`
`
`
`See claim 1.
`
`
`
`
`
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`8
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`IPR Page 10/23
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`
`Claims of U.S. Patent No.
`5,886,035
`which is 16-phenoxy-15-deoxy-15,15-
`difluoro-17,18,19,20-
`tetranorprostaglandin F2α, 16-(3-
`chlorophenoxy)-15-deoxy-15,15-
`difluoro-17,18,19,20-
`tetranorprostaglandin F2α, 16-phenoxy-
`15-deoxy-15,15-difluoro-13,14-dihydro-
`17,18,19,20-tetranorprostaglandin F2α
`or an alkyl ester or a salt thereof.
`Claim 4
`A medicine containing the compound
`according to claim 1 as an active
`ingredient.
`Claim 5
`The medicine according to claim 4,
`which is a preventive or therapeutic
`medicine for an eye disease.
`
`Claim 6
`The medicine according to claim 5,
`wherein the eye disease is glaucoma or
`ocular hypertension.
`
`Claim 7
`The medicine according to claim 4, 5 or
`6,
`
`Zioptan® and Tapros
`
`Tafluprost is an alkyl (isopropyl) ester
`of 16-phenoxy-15-deoxy-15,15-
`difluoro-17,18,19,20-
`tetranorprostaglandin F2α.
`
`
`Zioptan® and Tapros are medicines
`containing the compound of claim 1 as
`the active ingredient.
`
`See claim 4.
`Zioptan® and Tapros are preventive or
`therapeutic medicines for glaucoma or
`ocular hypertension, both of which are
`eye diseases. Ex.2032, 1; Ex.2044, 1.
`
`See claim 5.
`Zioptan® and Tapros are preventive or
`therapeutic medicines for glaucoma or
`ocular hypertension. Ex.2032, 1;
`Ex.2044, 1.
`
`See claims 4, 5, and 6.
`
`
`
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`9
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`IPR Page 11/23
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`
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`Claims of U.S. Patent No.
`5,886,035
`wherein A is an ethylene group or a
`vinylene group.
`
`Zioptan® and Tapros
`
`Tafluprost contains a vinylene group at
`the A position, as seen below:
`
`Claim 8
`The medicine according to claim 4, 5 or
`6,
`wherein X is —CH2—.
`
`
`
`
`
`See claims 4, 5, and 6.
`
`Tafluprost contains —CH2— at the X
`position, as seen below:
`
`Claim 9
`The medicine according to claim 4, 5 or
`6,
`
`
`
`
`
`See claims 4, 5, and 6.
`
`
`
`
`10
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`IPR Page 12/23
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`Claims of U.S. Patent No.
`5,886,035
`wherein both R2 and R3 are hydrogen
`atoms.
`
`Zioptan® and Tapros
`
`Tafluprost contains hydrogen atoms at
`each of the R2 and R3 positions, as seen
`below:
`
`Claim 10
`The medicine according to claim 4, 5 or
`6,
`wherein Z is —OR4.
`
`
`
`
`
`See claims 4, 5, and 6.
`
`Tafluprost contains an isopropoxy
`group, which is encompassed by —OR4,
`at the Z position, as seen below:
`
`Claim 11
`The medicine according to claim 9,
`
`
`
`See claim 9.
`
`
`
`
`
`
`11
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`IPR Page 13/23
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`
`
`Claims of U.S. Patent No.
`5,886,035
`wherein R1 is a phenoxymethyl group, a
`3,5-dichlorophenoxymethyl group or a
`3-chlorophenoxymethyl group.
`
`Zioptan® and Tapros
`
`Tafluprost contains a phenoxymethyl
`group at the R1 position, as seen below:
`
`Claim 12
`A medicine containing 16-phenoxy-15-
`deoxy-15,15-difluoro-17,18,19,20-
`tetranorprostaglandin F2α, 16-(3-
`chlorophenoxy)-15-deoxy-15,15-
`difluoro-17,18,19,20-
`tetranorprostaglandin F2α, 16-phenoxy-
`15-deoxy-15,15-difluoro-13,14-dihydro-
`17,18,19,20-tetranorprostaglandin F2α
`or an alkyl ester or salt thereof as an
`active ingredient.
`Claim 13
`The medicine according to claim 12,
`which is a preventive or therapeutic
`medicine for an eye disease.
`
`Claim 14
`The medicine according to claim 13,
`wherein the eye disease is glaucoma or
`ocular hypertension.
`
`
`
`
`
`
`Zioptan® and Tapros are medicines
`containing tafluprost, which is an alkyl
`(isopropyl) ester of 16-phenoxy-15-
`deoxy-15,15-difluoro-17,18,19,20-
`tetranorprostaglandin F2α.
`
`
`See claim 12.
`Zioptan® and Tapros are preventive or
`therapeutic medicines for glaucoma or
`ocular hypertension, both of which are
`eye diseases. Ex.2032, 1; Ex.2044, 1.
`
`See claim 13.
`Zioptan® and Tapros are preventive or
`therapeutic medicines for glaucoma or
`ocular hypertension. Ex.2032, 1;
`Ex.2044, 1.
`
`
`
`
`12
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`IPR Page 14/23
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`12.
`
` The tafluprost commercial embodiments have been commercially
`
`successful, evidencing the nonobviousness of the claimed invention. For the year
`
`ended March 31, 2018, Tapros sales are forecasted to be 18,083,000,000 JPY, or
`
`over $164 million. Ex.2030, 10. Those sales represented approximately a 10%
`
`increase over the previous year's sales of about $150 million (which were, in turn,
`
`approximately 5% higher than the year ended March 31, 2016). Id.
`
`13. Further, two generic manufacturers, Petitioner and Sandoz, are
`
`seeking to release generic versions of tafluprost in the US. Ex.2045; Ex.2046. But
`
`for the commercial success of Patents Owner's taflupost products, those companies
`
`would not be interested in making a generic copy.
`
`14. The commercial success of the products is a direct result of the
`
`claimed compound.
`
`B. Unexpected Results
`
`15. Tafluprost provided unexpected results over Compound C of Klimko,
`
`the closest prior art identified by Petitioner. For example, the '035 Patent
`
`establishes that tafluprost is effective at lowering IOP without the unacceptable
`
`hyperemia and initial increase in IOP after administration reported for Compound
`
`C. See Ex.2001, ¶¶35-37. The lack of an initial increase in IOP with tafluprost
`
`was further confirmed in papers characterizing tafluprost. Ex.2031, 6 (Figure 3).
`
`As Dr. Fechtner points out, only approximately 1% of patients that are treated with
`
`
`
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`13
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`IPR Page 15/23
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`Zioptan®/tafluprost discontinued their therapy due to ocular adverse reactions,
`
`including hyperemia. Ex.2029, ¶10 (citing Ex.2032, 2).
`
`16. A POSITA would not have reasonably expected fluorination at C15 to
`
`restore IOP-lowering activity. As of December 26, 1996, the prevailing view in
`
`the art was that the C15 hydroxyl group was important for binding to prostaglandin
`
`receptors for lowering IOP. As of that time, a POSITA also would have expected
`
`that C15 fluorination would significantly change the properties of a prostaglandin
`
`analog. As Klimko's inventor reported to still be true in 2004 (many years after the
`
`invention of the '035 Patent), "[t]he replacement of the carbon 15-hydroxyl group
`
`of PGF2α with a fluorine atom should profoundly affect many physicochemical
`
`properties of the molecule." Ex.2021, 1. The broad genus of allegedly inventive
`
`compounds in Klimko does not even allow for C15-fluorinated compounds.
`
`Ex.1003, 4:14-40.
`
`17. The different properties of C15 hydroxyl and C15 fluorine are
`
`numerous, including capacity for being a hydrogen bond donor and/or acceptor,
`
`Van der Waals radius, length of bond to the carbon, electronegativity, lipophilicity
`
`and effect on rotational conformation stability.
`
`18. A POSITA understood that a hydroxyl group can be a hydrogen bond
`
`donor and/or acceptor (with respect to binding to a receptor), whereas fluorine is
`
`incapable of being a hydrogen bond donor, and is only a very poor hydrogen bond
`
`
`
`
`14
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`IPR Page 16/23
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`acceptor. Dunitz et al., "Organic Fluorine Hardly Ever Accepts Hydrogen Bonds,"
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`Chem. Eur. J. 3(1):89-98 (1997) (Ex.2047), 1 ("covalently bound fluorine . . .
`
`hardly ever acts as a hydrogen-bond acceptor").
`
`19. Fluorine is more compact than the oxygen of the hydroxyl (Van der
`
`Waals radius of 1.47 and 1.52 Å, respectively), before accounting for the hydrogen
`
`(1.2 Å) that is also present in the hydroxyl. Carey and Sundberg, "3:
`
`Conformational, Steric, and Stereoelectronic Effects," in Advanced Organic
`
`Chemistry, Part A: Structure and Mechanism (2nd ed. 1984) (Ex.2048), 22.
`
`20. Similarly, a carbon-fluorine bond is shorter than the carbon-oxygen
`
`bond of the hydroxyl (1.39 and 1.43 Å) before adding the length of the oxygen-
`
`hydrogen bond of the hydroxyl. Ex.1008 (Bezuglov 1986), 4.
`
`21. A hydroxyl has an electronegativity of ~3.5; in contrast, fluorine has
`
`the highest electronegativity of any element (4.0). Id.
`
`22. Substitution of fluorine in place of a hydroxyl was well known to
`
`increase lipophilicity of the prostaglandin analog compound. Id., 3 ("such
`
`substitution increases lipophilicity of the molecule").
`
`23. Compared to a C15 hydroxyl, a C15 fluorine limits rotational
`
`conformation between C14 and C15 of PGF2α. Ex.2048, 52 (conformation limited
`
`by presence of fluorine and another electronegative substituent, e.g., oxygen or
`
`unsaturated carbon, bound to the same carbon).
`
`15
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`IPR Page 17/23
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`24. Therefore, a POSITA would have doubted that fluorine could mimic
`
`the C15 hydroxyl group of a prostaglandin analog, and a POSITA would have
`
`expected reduced IOP lowering activity due to C15 fluorination. Difluorination
`
`would have been considered an even more radical departure from the active C15
`
`hydroxyl.
`
`C. Long-Felt but Unmet Need
`
`25. Tafluprost is the only commercially available C15-difluorinated
`
`compound. Tafluprost exhibits a unique receptor profile. For example, tafluprost
`
`is highly selective for the FP receptor; tafluprost's affinity for the FP receptor is 12
`
`times greater than latanoprost, with little to no affinity for other receptors.
`
`Ex.2031, 4-5. I understand from Dr. Fechtner that, as of December 26, 1996,
`
`tafluprost's unique receptor profile and associated properties filled a previously
`
`long-felt but unmet need for an effective prostaglandin analog that can be tolerated
`
`by patients unable to tolerate other prostaglandin analogs. Ex.2029, ¶¶6-10.
`
`D.
`
`Failure of Others
`
`26.
`
`I also understand from Dr. Fechtner that other glaucoma medications
`
`have been unsuccessful in the market because of intolerable side effects (such as
`
`hyperemia and allergy), or poor efficacy. Ex.2029, ¶11.
`
`
`
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`16
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`DECLARATION
`
`I declare that all statements made herein on my own knowledge are true and
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`that all statements made on information and belief are believed to be true, and
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`further, that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Executed in alttwlUilt/Slltflt V4on this it: day ofMarch 2018.
`
`22/” E £5? £2
`
`Timothy L. Macdonald, PhD.
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`IPR Page 19/23
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`IPR Page 19/23
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`
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`Exhibit B
`Exhibit B
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`IPR Page 20/23
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`IPR Page 20/23
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`
`
`Exhibit
`No.
`
`Updated List of Materials Considered
`
`Document
`
`N/A
`
`N/A
`
`1007
`
`1008
`
`1012
`
`1026
`
`Petition for Inter Partes Review of U.S. Patent No. 5,886,035 by
`Micro Labs Ltd. (IPR2017-04343)
`Institution Decision for Inter Partes Review of U.S. Patent No.
`5,886,035 by Micro Labs Ltd. (IPR2017-04343) (Paper 11)
`1001 U.S. Patent No. 5,886,035
`1002
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`IPR Page 22/23
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`and Oak Pharmaceuticals, Inc. v. Micro Labs Limited and Micro Labs
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`
`2030
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`2031
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`2032
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`2034
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`
`
`
`
`IPR Page 23/23
`
`
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